The UT Houston Substance Abuse Research-Medication Development Center (SAR-MDC) is currently in its 15th year of funding. During the previous funding period, the focus of the Center was on agonist or replacement therapy for cocaine dependence using stimulant and stimulant-like medications. For this competing renewal of our Center, the theme advances to examining behavioral and neurochemical mechanisms of replacement therapy to drive novel medication development for cocaine dependence. The research is a collaborative, interdisciplinary effort in behavioral laboratory, brain imaging, and outpatient clinical trials using novel medications, novel imaging methodologies, and novel clinical trial designs that will provide a greater understanding of the behavioral neurobiology of cocaine dependence and lead to effective pharmacotherapies for the disorder. The aims of the Center will be achieved through two cores and five projects. The Administrative Core (F. Gerard Moeller PI) serves as a general resource for the other projects and the Advanced Clinical Design and Statistical Analysis Core. The Advanced Clinical Design and Statistical Analysis Core (Charles Green PI) will provide advanced statistical analysis and study design support to the other projects of the Center as well as other NIDA funded projects outside the Center. Project 1 (Joy M. Schmitz PI) is a Phase II adaptive design clinical trial using the selective adenosine A2A receptor antagonist SYN115 alone and in combination with the dopamine precursor L-Dopa. Project 2 (Scott D. Lane PI) is a behavioral laboratory study that characterizes the psychopharmacological properties of novel medications including the adenosine A2A receptor antagonist SYN115. Measurement will focus on drug discrimination, subjective effects, behavioral inhibition and decision making. Project 3 (Joy M. Schmitz PI) is a Phase II clinical trial that will study the efficacy of combination serotonin/dopamine pharmacotherapy in cocaine dependent subjects with Bayesian subgroup analyses. Project 4 (F. Gerard Moeller PI) is a human imaging project utilizing fMRI and DTI as predictors of treatment response of subjects in Projects 1 and 3. Project 5 (Ponnada A. Narayana PI) is a rodent imaging project utilizing DTI and brain neurohistology to study effects of chronic cocaine administration on brain structure and potential amelioration of these effects using the adenosine A2A receptor antagonist SYN115.